Brain Melanocortin Control of Activity Energy Expenditure and Obesity Resistance It is becoming widely accepted that individual differences in daily physical activity levels are inherited, and that extended inactivity can lead to weight gan and metabolic dysfunction. We have found consistently high levels of physical activity and energy expenditure in rats selectively bred for high intrinsic aerobic capacity (i.e., the ability o run long distances without prior training; HCR) compared to their low-capacity counterparts (LCR); these differences are not dependent on body mass or composition. Moreover, HCR have higher total daily energy expenditure than LCR, a result of higher non-resting (not resting) energy expenditure. Here, we hypothesize that differences in the brain melanocortin system, specifically site-specific variations in melanocortin receptor (MCR) expression, may underlie the high- and low-activity phenotypes. We will engage undergraduate research trainees in testing this hypothesis, utilizing rat models of leanness/obesity derived through artificial selection as well as through deletion of gene expression for a specific MCR. First, we will determine how differences in brain expression patterns of MCR may contribute to physical activity energy expenditure, focusing on MCR 3, 4, and 5, as well quantify how activity energy expenditure is altered in MC4R- deficient rats. Next, we will probe the molecular mechanisms underlying the ability of brain MC to increase skeletal muscle fuel utilization during physical activity, and determine if these mechanisms differ between HCR and LCR. Lastly, we will determine if caloric restriction (i.e., dieting), which causes more weight loss in high- activity HCR than in low-activiy LCR, differentially alters brain MCR and skeletal muscle gene expression patterns in HCR compared to LCR; we will also test this hypothesis using MC4R-deficient rats. Focusing on identifying unique features of central (brain) and peripheral (e.g., skeletal muscle) control of energy balance in the lean phenotype may yield novel treatments for obesity.